This study aims to determine the resilient and vulnerable components in the aging- or disease-induced functional decline of neuromuscular transmission, using the powerful Drosophila genetic model system. An integrated approach at the molecular, cellular, and circuit levels can reveal the roles of key genes that exert critical influences on the aging process, including Sod, whose homologue in humans is implicated in Amyotrophic Lateral Sclerosis (ALS or Lou Gherig's disease). We found a striking, robust life-span extension and improved motor ability through social interaction in Sod mutants upon co-housing with younger, active flies. These plastic phenotypes, readily quantified and manipulated, provide a sensitized system to unravel the major interacting genetic networks underlying the aging process and to identify potential neuroprotection mechanisms against the functional decline in neuromuscular transmission. To facilitate the study of the neuromuscular junction (NMJ) in aging adults, we recently developed a dissected preparation of adult abdominal NMJs that is accessible to paradigms and manipulations previously established for larval NMJs that have elucidated much of the genetic, molecular and cellular bases. A multidisciplinary approach with the tools and protocols developed in our labs will facilitate correlation of data at different levels, using transgenic flies for targeted expression or disruptin in pre- and post-synaptic neurons, muscle, and glia. Our Aims are: (1) Systematic studies on the aging-susceptible and aging-resilient physiological parameters to uncover the underlying cellular and molecular mechanisms of age-related functional decline in the new adult abdominal NMJ preparation. We will correlate electrophysiological and optical imaging measurements to reveal major modifications in presynaptic motor axon terminals, synaptic contacts, and postsynaptic muscle during aging. (2) Impacts of hyperexcitability mutations on age-related decline of NMJ function using mutants that have been well studied in larval NMJ and adult escape and flight circuits. Neuronal hyperexcitability has been implicated along with ROS stress in aging neurons. We will analyze pre- and post-synaptic elements using several hyperexcitability mutants of K+ channels implicated in ROS stress sensitivity or redox regulation, including the redox-senstive Sh IA and slo BK channels. (3) Centering on Sod, we will ask: i) how Sod and related mutations in redox regulation modify the progression of NMJ functional decline; and ii) how interacting genes of Sod act in a genetic network. We will investigate how modifications in NMJ properties reflect the striking plasticity of Sod phenotypes through social interaction. Integration of result from molecular investigations, neuronal and circuit physiology, and automated behavioral analysis will facilitate the discovery of key Sod interacting genes and may reveal promising targets for neuroprotective manipulations.